Dithiaarsanes Induce Oxidative Stress-Mediated Apoptosis in HL-60 Cells by Selectively Targeting Thioredoxin Reductase

The selenoprotein thioredoxin reductase (TrxR) plays a pivotal role in regulating cellular redox homeostasis and has attracted increasing attention as a promising anticancer drug target. We report here that 2-(4-aminophenyl)-1,3,2-dithiarsinane (PAO–PDT, <b>4</b>), a potent and highly selective small molecule inhibitor of TrxR, stoichiometrically binds to the C-terminal selenocysteine/cysteine pair in the enzyme in vitro and induces oxidative stress-mediated apoptosis in HL-60 cells. The molecular action of <b>4</b> in cells involves inhibition of TrxR, elevation of reactive oxygen species, depletion of cellular thiols, and activation of caspase-3. Knockdown of TrxR sensitizes the cells to <b>4</b> treatment, whereas overexpression of the functional enzyme alleviates the cytotoxicity, providing physiological relevance for targeting TrxR by <b>4</b> in cells. The simplicity of the structure and the presence of an easily manipulated amine group will facilitate the further development of <b>4</b> as a potential cancer chemotherapeutic agent.